The present invention, in some embodiments thereof, relates to sensing and, more particularly, but not exclusively, to a methods and system for detecting a marker, such as, but not limited to, a biomarker, in a liquid, such as, but not limited to, biological liquid.
The development of efficient bio-molecular separation and purification techniques is of high importance in modern genomics, proteomics, and bio-sensing areas, primarily due to the fact that most bio-samples are mixtures of high diversity and complexity. Most of the currently-practiced techniques lack the capability to rapidly and selectively separate and concentrate specific target proteins from a complex bio-sample, and are difficult to integrate with lab-on-a-chip sensing devices.
Semiconducting nanowires are known to be extremely sensitive to chemical species adsorbed on their surfaces. For a nanowire device, the binding of a charged analyte the surface of the nanowire leads to a conductance change, or a change in current flowing through the wires. The 1D (one dimensional) nanoscale morphology and the extremely high surface-to-volume ratio make this conductance change to be much greater for nanowire-based sensors versus planar FETs (field-effect transistors), increasing the sensitivity to a point that single molecule detection is possible.
Nanowire-based field-effect transistors (NW-FETs) have therefore been recognized in the past decade as powerful potential new sensors for the detection of chemical and biological species. See, for example, Patolsky et al., Analytical Chemistry 78, 4260-4269 (2006); Stern et al., IEEE Transactions on Electron Devices 55, 3119-3130 (2008); Cui et al., Science 293, 1289-1292 (2001); Patolsky et al. Proceedings of the National Academy of Sciences of the United States of America 101, 14017-14022 (2004), all being incorporated by reference as if fully set forth herein.
Studies have also been conducted with nanowire electrical devices for the simultaneous multiplexed detection of multiple biomolecular species of medical diagnostic relevance, such as DNA and proteins [Zheng et al., Nature Biotechnology 23, 1294-1301 (2005); Timko et al., Nano Lett. 9, 914-918 (2009); Li et al., Nano Lett. 4, 245-247 (2004)].
Generally, in a NW-FET configuration, the gate potential controls the channel conductance for a given source drain voltage (VSD), and modulation of the gate voltage (VGD) changes the measured source-drain current (ISD). For NW sensors operated as FETs, the sensing mechanism is the field-gating effect of charged molecules on the carrier conduction inside the NW. Compared to devices made of micro-sized materials or bulk materials, the enhanced sensitivity of nanodevices is closely related to the reduced dimensions and larger surface/volume ratio. Since most of the biological analyte molecules have intrinsic charges, binding on the nanowire surface can serve as a molecular gate on the semiconducting SiNW [Cui et al., 2001, supra].
Antibody/enzyme nanowire FET devices which target metabolites via binding affinity have been disclosed in, for example, Lu et al. Bioelectrochemistry 2007, 71(2): 211-216; Patolsky et al. Nanowire-based biosensors. Anal Chem 2006, 78(13): 4260-4269; and Yang et al. Nanotechnology 2006, 17(11): S276-S279.
Electrochemically-sensitive nanowire sensors for detecting metabolites by oxidative reactions have been disclosed in, for example, Lu et al. Biosens Bioelectron 2009, 25(1): 218-223; Shao et al. Adv Funct Mater 2005, 15(9): 1478-1482; Su et al. Part Part Syst Char 2013, 30(4): 326-331; and Tyagi et al. Anal Chem 2009, 81(24): 9979-9984.
U.S. Pat. No. 7,619,290, U.S. Patent Application having publication No. 2010/0022012, and corresponding applications, teach nanoscale devices composed of, inter alia, functionalized nanowires, which can be used as sensors.
Clavaguera et al. disclosed a method for sub-ppm detection of nerve agents using chemically functionalized silicon nanoribbon field-effect transistors [Clavaguera et al., Angew. Chem. Int. Ed. 2010, 49, 1-5].
SiO2 surface chemistries were used to construct a ‘nano-electronic nose’ library, which can distinguish acetone and hexane vapors via distributed responses [Nature Materials Vol. 6, 2007, pp. 379-384].
U.S. Patent Application having Publication No. 2010/0325073 discloses nanodevices designed for absorbing gaseous NO. WO 2011/000443 describes nanodevices which utilize functionalized nanowires for detecting nitro-containing compounds.
Duan et al. [Nature Nanotechnology, Vol. 7, 2012, pp. 174-179] describes a silicon nanowire FET detector and an electrically insulating SiO2 nanotube that connects the FET to the intracellular fluid (the cytosol). When there is a change in transmembrane potential Vm, the varying potential of the cytosol inside the nanotube gives rise to a change in the conductance G of the FET.
Kosaka et al. [Nature Nanotechnology, Vol. 9, 2014, pp. 1047-1053] discloses detection of cancer biomarkers in serum using surface-anchored antibody.
Krivitsky et al. [Nano letters 2012, 12(9): 4748-4756] describe an on-chip all-SiNW filtering, selective separation, desalting, and preconcentration platform for the direct analysis of whole blood and other complex biosamples. The separation of required protein analytes from raw bio-samples is first performed using a antibody-modified roughness-controlled SiNWs forest of ultralarge binding surface area, followed by the release of target proteins in a controlled liquid media, and their subsequent detection by SiNW-based FETs arrays fabricated on the same chip platform.
WO 2015/059704 discloses an integrated microfluidic nanostructure sensing system, comprised of one or more sensing compartments featuring a redox-reactive nanostructure FET array which is in fluid communication with one or more sample chambers. This system has been shown to perform multiplex real-time monitoring of cellular metabolic activity in physiological solutions, and was demonstrated as an efficient tool in promoting the understanding of metabolic networks and requirements of cancers for personalized medicine.
Additional background art includes, for example, Chen et al., Nano Today (2011) 6, 131-54, and references cited therein; and Stern et al., Nature Nanotechnology, 2009.